Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulaci on Card ıaca y Electrofisiolog ıa (SOLEACE) Gregory Y. H. Lip 1 *, Jean Philippe Collet 2 , Raffaele de Caterina 3 , Laurent Fauchier 4 , Deirdre A. Lane 5 , Torben B. Larsen 6 , Francisco Marin 7 , Joao Morais 8 , Calambur Narasimhan 9 , Brian Olshansky 10 , Luc Pierard 11 , Tatjana Potpara 12 , Nizal Sarrafzadegan 13 , Karen Sliwa 14 , Gonzalo Varela 15 , Gemma Vilahur 16 , Thomas Weiss 17 , Giuseppe Boriani 18 and Bianca Rocca 19 ESC Scientific Document Group: Bulent Gorenek 20 (Reviewer Coordinator), Irina Savelieva 21 , Christian Sticherling 22 , Gulmira Kudaiberdieva 23 , Tze-Fan Chao 24 , Francesco Violi 25 , Mohan Nair 26 , Leandro Zimerman 27 , Jonathan Piccini 28 , Robert Storey 29 , Sigrun Halvorsen 30 , Diana Gorog 31 , Andrea Rubboli 32 , Ashley Chin 33 and Robert Scott-Millar 34 * Corresponding author. Tel/fax: þ44 121 5075503. E-mail address: g.y.h.lip@bham.ac.uk Published on behalf of the European Society of Cardiology. All rights reserved. V C The Author 2017. For permissions, please email: [email protected]. Europace (2017) 19, 1757–1758 EHRA CONSENSUS DOCUMENT doi:10.1093/europace/eux240 Downloaded from https://academic.oup.com/europace/article-abstract/19/11/1757/4098134 by guest on 25 August 2018
Transcript
Antithrombotic therapy in atrial fibrillation
associated with valvular heart disease: a joint
consensus document from the European
Heart Rhythm Association (EHRA) and
European Society of Cardiology Working
Group on Thrombosis, endorsed by the ESC
Working Group on Valvular Heart Disease,
Cardiac Arrhythmia Society of Southern
Africa (CASSA), Heart Rhythm Society (HRS),
Asia Pacific Heart Rhythm Society (APHRS),
South African Heart (SA Heart) Association
and Sociedad Latinoamericana de
Estimulaci�on Card�ıaca y Electrofisiolog�ıa(SOLEACE)
Gregory Y. H. Lip1*, Jean Philippe Collet2, Raffaele de Caterina3,
Laurent Fauchier4, Deirdre A. Lane5, Torben B. Larsen6, Francisco Marin7,
Joao Morais8, Calambur Narasimhan9, Brian Olshansky10, Luc Pierard11,
Tatjana Potpara12, Nizal Sarrafzadegan13, Karen Sliwa14, Gonzalo Varela15,
Gemma Vilahur16, Thomas Weiss17, Giuseppe Boriani18 and Bianca Rocca19
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1Institute of Cardiovascular Sciences, University of Birmingham and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Denmark (Chair,representing EHRA); 2Sorbonne Universite Paris 6, ACTION Study Group, Institut De Cardiologie, Groupe Hopital Pitie-Salpetriere (APHP), INSERM UMRS 1166, Paris, France;3Institute of Cardiology, ‘G. D’Annunzio’ University, Chieti, Italy; 4Centre Hospitalier Universitaire Trousseau et Faculte de Medicinde, Universite Francois Rabelais, Tours,France; 5Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom; and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, AalborgUniversity, Aalborg, Denmark; 6Thrombosis Research Unit,Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark; 7Hospital Universitario Virgen de laArrixaca, Murcia, Spain; 8Department of Cardiology, Leiria Hospital Centre, Leiria, Portugal; 9Department of Cardiac Electrophysiology, Care Hospital, Hyderabad, India; 10MercyHospital, Mason City, Iowa, USA; 11Department of Cardiology, University Hospital Sart-Tilman, Liege, Belgium; 12School of Medicine, Belgrade University; Cardiology Clinic,Clinical Center of Serbia, Belgrade, Serbia; 13Isfahan Cardiovascular Research Center (WHO Collaborating Center), Cardiovascular Research Institute, Isfahan University ofMedical Sciences, Isfahan, Iran and School of Population and Public Health, University of British Columbia, Vancouver, Canada; 14Hatter Institute for Cardiovascular Research inAfrica, Faculty of Health Sciences, University of Cape Town, South Africa; and Mary McKillop Institute, ACU, Melbourne, Australia; 15Servicio de Electrofisiolog�ıa, CentroCardiovascular Casa de Galicia, Hidalgos, Uruguay; 16Cardiovascular Science Institute - ICCC, IIB-Sant Pau, CiberCV, Hospital de Sant Pau, Barcelona, Spain; 17MedicalDepartment For Cardiology and Intensive Care, Wilhelminenhospital, and Medical Faculty Sigmund Freud University, Vienna, Austria; 18Cardiology Department, University ofModena and Reggio Emilia, Policlinico di Modena, Modena, Italy; 19Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy (Co-Chair, representing ESCWorking Group on Thrombosis); 20Eskisehir Osmangazi University, Eskisehir, Turkey (Reviewer Coordinator); 21Molecular and Clinical Sciences Institute, St George’s Universityof London, London, UK; 22Department of Cardiology University Hospital Basel, Basel, Switzerland; 23Adana, Turkey; 24Division of Cardiology, Department of Medicine, TaipeiVeterans General Hospital, and Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan (APHRS reviewer);25University of Rome La Sapienza, Rome, Italy; 26Department of Cardiology, Max Super Specialty Hospital, New Delhi, India; 27Hospital de ClUnicas de Porto Alegre, FederalUniversity of Rio Grande do Sul, Brasil (SOLAECE reviewer); 28Duke University Medical Center, Duke Clinical Research Institute, Durham, USA (HRS reviewer);29Department of Cardiovascular Sciences, University of Sheffield, Sheffield, UK; 31Department of Cardiology, Oslo University Hospital Ulleval, Oslo, Norway; 30National Heartand Lung Institute, Imperial College, London, and Postgraduate Medicine, University of Hertfordshire, Hertfordshire, UK; 32Ospedale Maggiore, Division of Cardiology,Bologna, Italy (Working Group of Thrombosis reviewer); 33Electrophysiology and Pacing, Groote Schuur Hospital, University of Cape Town, South Africa (CASSA reviewer);and 34Department of Medicine, Division of Cardiology, University of Cape Town, South Africa (SAHeart reviewer)
Received 14 June 2017; editorial decision 15 June 2017; accepted 20 June 2017; online publish-ahead-of-print 30 August 2017
Atrial fibrillation (AF) is a major worldwide public health problem, and AF in association with valvular heart disease (VHD) is also com-mon. However, management strategies for this group of patients have been less informed by randomized trials, which have largely focusedon ‘non-valvular AF’ patients.Thrombo-embolic risk also varies according to valve lesion and may also be associated with CHA2DS2VASc score risk factor components,rather than only the valve disease being causal.Given marked heterogeneity in the definition of valvular and non-valvular AF and variable management strategies, including non-vitamin Kantagonist oral anticoagulants (NOACs) in patients with VHD other than prosthetic heart valves or haemodynamically significant mitralvalve disease, there is a need to provide expert recommendations for professionals participating in the care of patients presenting with AFand associated VHD.To address this topic, a Task Force was convened by the European Heart Rhythm Association (EHRA) and European Society ofCardiology (ESC) Working Group on Thrombosis, with representation from the ESC Working Group on Valvular Heart Disease, HeartRhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and SociedadLatinoamericana de Estimulaci�on Card�ıaca y Electrofisiolog�ıa (SOLEACE) with the remit to comprehensively review the published evi-dence, and to publish a joint consensus document on the management of patients with AF and associated VHD, with up-to-date consen-sus recommendations for clinical practice for different forms of VHD.This consensus document proposes that the term ‘valvular AF’ is outdated and given that any definition ultimately relates to theevaluated practical use of oral anticoagulation (OAC) type, we propose a functional Evaluated Heartvalves, Rheumatic or Artificial(EHRA) categorization in relation to the type of OAC use in patients with AF, as follows: (i) EHRA Type 1 VHD, which refers to AF patientswith ‘VHD needing therapy with a Vitamin K antagonist (VKA); and (ii) EHRA Type 2 VHD, which refers to AF patients with ‘VHD need-ing therapy with a VKA or a Non-VKA oral anticoagulant (NOAC)’, also taking into consideration CHA2DS2VASc score risk factor com-ponents.This consensus document also summarizes current developments in the field, and provides general recommendations for the managementof these patients based on the principles of evidence-based medicine....................................................................................................................................................................................................
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Preamble and valvular heartdisease definition
Atrial fibrillation (AF) is a major public health problem1 with globalprevalence rates (per 1000000 population) in 2010 being 596.2(95% uncertainty interval (UI), 558.4–636.7) in men and 373.1(95% UI, 347.9–402.2) in women; the incidence rates increasedto 77.5 (95% UI, 65.2–95.4) in men and 59.5 (95% UI, 49.9–74.9)in women.2 Worldwide, AF in association with valvular heart dis-ease (VHD) is also common, and management strategies forthis group of patients have been less addressed by randomizedtrials. The latter have largely focused on ‘non-valvular AF’ patientsleading to major uncertainties over how to define (and treat) suchpatients.
There is also an important heterogeneity in the definition of valvu-lar and non-valvular AF.3 Some physicians assume that any valve dis-ease should be considered as ‘valvular’ AF. Others consider that onlymechanical valve prosthesis and rheumatic mitral stenosis should bedefined as ‘valvular’ AF.
The term valvular AF has been arbitrarily applied and the 2016ESC guidelines have avoided the term ‘valvular AF’ and refer sim-ply to ‘AF related to hemodynamically significant mitral stenosisor prosthetic mechanical heart valves’.4 AF clearly leads to anincremental risk for thromboembolism in patients with mitralvalve stenosis, but there are limited data for other valvular dis-eases. Another proposal is to use the acronym MARM-AF as asimple acronym to designate ‘Mechanical and Rheumatic MitralAF’ as an alternative to term ‘valvular AF’ to designate the clinicalscenarios for which at the non-vitamin K antagonist oral anticoa-gulants (NOACs) are not indicated.5
For this document we recognize the uncertainty in terminology,and our scope largely relates to AF related to ‘hemodynamically sig-nificant’ rheumatic VHD (ie. severe enough to impact on patient’ssurvival or necessitates an intervention or surgery) or prostheticmechanical heart valves. Nonetheless, thrombo-embolic (TE) riskvaries according to valve lesion and may be associated withCHA2DS2VASc score risk factor components, rather than the valvedisease per se being causal.6,7 TE risk may also be influenced not onlyby type but also the severity of the lesion. For example, the degree ofmitral regurgitation may matter when it comes to risk of TE as somestudies suggest that mild (Grade 1) mitral regurgitation is associatedwith a 2.7-fold increased risk of stroke/TE, while severe forms maypossibly have a ‘protective’ effect (HR = 0.45 for stroke and 0.27 forLA stasis.8 An appropriate definition of ‘valvular AF’ would need toidentify a subgroup of patients with similar pathophysiology ofthrombo-embolism, TE risk, and treatment strategies6,9; however,this would be challenging given the major heterogeneity of thecondition.
This consensus document proposes that the term ‘valvular AF’ isoutdated and given that any definition ultimately relates to the eval-uated practical use of oral anticoagulation (OAC) type, we propose afunctional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) cat-egorization in relation to the type of OAC use in patients with AF, asfollows:
Evaluated Heartvalves, Rheumatic or Artificial (EHRA) Type 1,which refers to AF patients with ‘VHD needing therapy with aVitamin K antagonist (VKA)’
[EHRA Type I VHD is broadly similar to the previously describedMARM-AF.]
Evaluated Heartvalves, Rheumatic or Artificial (EHRA) Type 2VHD, which refers to AF patients with ‘VHD needing therapy with aVKA or a NOAC’, also taking into consideration CHA2DS2VAScscore risk factor components:
This classification would have the advantage that it may easilyevolve or be updated (type 1 may become type 2 or vice versa)when there are new results. For example, transcatheter mitral valveinterventions (TMVI, e.g. to include both MitraClip and Mitral valvereplacement) are emerging as a possible therapeutic options,10 butmore data are awaited especially in relation to OAC use.
A recent physicians survey3 reported marked heterogeneity in thedefinition of valvular and non-valvular AF and variable managementstrategies, including NOACs in patients with VHD other than pros-thetic heart valves or haemodynamically significant mitral stenosis.Thus, there is a need to provide expert recommendations for profes-sionals participating in the care of patients presenting with AF andassociated VHD. These may include rheumatic VHD, mechanical orbiological prosthetic valves and percutaneous aortic valve implanta-tion (TAVI), as well as those having undergone mitral valve repair.Whilst hypertrophic cardiomyopathy is sometimes discussed in asso-ciation with valvular AF, this would not be addressed in this document,given specific guidelines on the management of this condition.11
To address this topic, a Task Force was convened by the EuropeanHeart Rhythm Association (EHRA) and European Society ofCardiology (ESC) Working Group on Thrombosis, with representa-tion from the ESC Working Group on Valvular Heart Disease, HeartRhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS),South African Heart (SA Heart) Association and SociedadLatinoamericana de Estimulaci�on Card�ıaca y Electrofisiolog�ıa(SOLEACE) with the remit to comprehensively review the publishedevidence, and to publish a joint consensus document on the manage-ment of patients with AF and associated VHD, with up-to-date con-sensus recommendations for clinical practice.
This document summarizes current developments in the field, andprovides general recommendations for the management of thesepatients based on the principles of evidence-based medicine.
Antithrombotic therapy in AF with valvular heart disease 1758a
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Rather than ‘valvular AF’ a more functional Evaluated Heartvalves,Rheumatic or Artificial (EHRA) categorization in relation to the typeof OAC use is recommended in patients with AF, as follows:
(i) EHRA Type 1 VHD, which refers to AF patients with ’VHDneeding therapy with a Vitamin K antagonist (VKA); and
(ii) EHRA Type 2 VHD, which refers to AF patients with‘VHD needing therapy with a VKA or a Non-VKA oralanticoagulant (NOAC), also taking into considerationCHA2DS2VASc score risk factor components.
Evidence reviewMembers of the Task Force were asked to perform a detailed litera-ture review, weigh the strength of evidence for or against a particulartreatment (or procedure), and include estimates of expected healthoutcomes where data exist. Patient-specific modifiers, comorbidities,and issues of patient preference that might influence the choice ofparticular tests or therapies are considered, as are frequency offollow-up and cost effectiveness. In controversial areas, or withregard to issues without evidence other than usual clinical practice, aconsensus was achieved by agreement of the expert panel after thor-ough deliberations. This document was prepared by the Task Forcewith representation from EHRA, HRS, APHRS, and SOLAECE. Thedocument was peer-reviewed by official external reviewers repre-senting EHRA, HRS, APHRS, and SOLAECE.
Consensus statements are evidence-based, and derived primarilyfrom published data. Current systems of ranking level of evidence arebecoming complicated in a way that their practical utility might be com-promised.12 We have, therefore, opted for an easier and, perhaps, moreuser-friendly system of ranking that should allow physicians to easilyassess current status of evidence and consequent guidance (Table 1).
Thus, a ‘green heart’ indicates a recommended statement or rec-ommended/indicated treatment (or procedure) and is based on atleast one randomized trial, or is supported by large observational evi-dence that it is beneficial and effective. A ‘yellow heart’ indicates gen-eral agreement and/or scientific evidence favouring a statement orthe usefulness/efficacy of a treatment or procedure. A yellow heartmay be supported by randomized trials based on small number ofpatients or not widely applicable. Treatment strategies for whichthere have been scientific evidence that they are potentially harmfuland should not be used are indicated by a ‘red heart’.
EHRA grading of consensus statements does not have separatedefinitions of Level of Evidence. The categorisation used for consen-sus statements (used in consensus documents) should not be consid-ered as being directly similar to that used for official society guidelinerecommendations which apply a classification (I–III) and level of evi-dence (A, B, and C) to recommendations in official guidelines.
Finally, this is a consensus document that includes evidence andexpert opinions from several countries. The anticoagulationapproaches discussed may, therefore, include drugs that do not havethe approval of governmental regulatory agencies in all countries.
Relationships with industry and otherconflictsIt is EHRA/ESC policy to sponsor position papers and guidelineswithout commercial support, and all members volunteered their
time. Thus, all members of the writing group as well as reviewershave disclosed any potential conflict of interest in detail, at the end ofthis document.
Epidemiology of valvular atrialfibrillation and implications forstroke/thrombo-embolism
The reported prevalence of AF varies by geographical region.2 InAustralian, North American and European studies, approximately1–2% of adults have AF.13–15 In Asians, the reported prevalence ofAF ranges from 0.1–4.0% in the community and 2.8–14% in hospital-based studies.16
Nonetheless, robust data on the epidemiology of patients with AFand associated VHD are limited. Examples of available data fromsome global registries and large trials are reported in Supplementarymaterial online, Table S1. In the RE-LY AF Registry which enrolledpatients presenting to an emergency department with AF at 164 sitesin 46 countries, rheumatic heart disease was present in 2.2% of NorthAmerican patients, in comparison with 21.5% in Africa and 31.5% inIndia7; interestingly thrombo-embolism rates were related to clinicalrisk profile, as expressed by CHADS2 score, irrespective of the pres-ence of rheumatic VHD. Detailed data on the geographic distributionof valvular AF are also reported in the Supplementary material online.
This categorization for our consensus document should not be considered asbeing directly similar to that used for official society guideline recommendationswhich apply a classification (I–III) and level of evidence (A, B, and C) torecommendations.
1758b G.Y.H. Lip
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Pathophysiology—a brief overview
There is a general agreement that AF is independently associated withthrombotic diathesis.17 The drivers include the three elements of theVirchow’s triad: blood flow alterations, endocardial injury and changes inblood constituents.18 In fact, according to the recently published EHRA/HRS/APHRS/SOLAECE consensus document, atrial tissue in VHD ischaracterized, at a histopathological level, by a combination of cardio-myocyte and fibrotic changes.19 Co-morbidities present in most AFpatients may contribute to enhance thrombotic risk by pro-inflamma-tory/pro-atherogenic mechanisms. An overview of the pathophysiology
of thrombogenesis in AF in haemodynamically significant mitral stenosisand/or mechanical heart valves prosthesisis shown in Figure 1.
The risk of TE is increased in patients with AF and mechanicalvalve, mild-to-severe mitral stenosis20 and left atrium dilatation, ascompared to non-valvular AF,6 suggesting differences among thepathogenic mechanisms contributing to thrombosis in each of theseAF conditions. It is generally thought that Virchow’s triad is triggeredby the turbulent flow and the endothelial injury that accompaniesvalvular AF. On top of this, AF prosthetic valves (particularly mechan-ical prosthesis) induce thrombin generation through the activation ofboth the tissue factor (TF) and the contact coagulation pathways.21
Figure 1 Pathophysiology of thrombogenesis in atrial fibrillation (AF) related prosthesis and/or mitral valve diseases. In valvular-AF there is a propen-sity to thrombosis because of the presence of the Virchow’s triad components which, in turn, are found likely boosted by patients’ co-morbid conditions.The risk of thrombosis, however, is enhanced because of the presence of prosthetic valves which activate the coagulation cascade (both the intrinsic andextrinsic pathway) leading to thrombin production (a strong platelet agonist); and, although to a lesser extent, because of the considerable degree ofmitral stenosis which induces flow turbulences capable of inducing platelet activation. Finally, AF also frequently occurs in patients with severe aorticstenosis, which can be associated to the Heyde’s syndrome due to Von Willebrand Factor (VWF) consumption leading to an acquired bleeding disorder.
Antithrombotic therapy in AF with valvular heart disease 1758c
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Surgical heart valve replacement surgery induces tissue damage withTF release leading to extrinsic coagulation pathway activation afterbinding to plasma Factor (F) VII/FVIIa. Moreover, the exposure ofvalve leaflets, struts and/or sewing ring to the circulating blood22 canactivate the contact (intrinsic) coagulation pathway. Both intrinsicand extrinsic pathways converge factor X (FX) activation and thenthe transformation of prothrombin into thrombin (FIIa) and forma-tion of the fibrin mesh. The vitamin K antagonist (VKA), warfarin, byblocking the formation of the vitamin K-dependent clotting FVII, FIX,FX, and FII prevents the activation of the coagulation cascade at theextrinsic and intrinsic pathway levels.
In addition to the thrombogenic contribution of plasma coagula-tion in valvular AF, platelet activation may possibly contribute,although to a much lesser extent, to promote thrombogenesis, par-ticularly in mild-to-severe mitral stenosis. It is also possible that mod-erate to severe mitral stenosis causes increased blood stasis, due tothe severe dilatation of the left atrium occurring in this condition.Finally, acquired type IIA von Willebrand disease and bleeding com-plications can be associated with severe aortic stenosis due to high-molecular weight multimer consumption.23
Oral anticoagulation with vitaminK antagonists in patients with AFand prosthetic heart valves,including bioprostheses
Mechanical heart valvesOral anticoagulation (OAC) with VKA is crucial for prevention of TEin patients with mechanical heart valves, regardless the presence orabsence of AF. The ESC guidelines24 establish the risk of TE in patientswith mechanical valves according to valve type and position, and alsoaccording to the individual patient risk profile or comorbidities.Warfarin and other VKA are the most widely used OACs, and aretitrated according to international normalized ratio (INR) range andtarget value which is also related with associated risk factors (Table 2).
The duration of antithrombotic therapy also varies according to anumber of factors. Lifelong anticoagulant treatment is indicated for allpatients with mechanical valves and those with bioprosthetic valvesor native valve disease with >_1 additional risk factors.
Clinical trials with VKA are sparse and recommendations aremostly based on old trials, with the oldest types of mechanical valveprostheses, and AF patients were excluded.
Patients with bioprostheses and additional risk factors for embo-lism (AF, venous TE, hypercoagulable state, or with a lesser degree ofevidence, severely impaired left ventricular function) require life-longOAC. The use of NOACs instead of warfarin in this setting isaccepted by the more recent document of recommendations byEHRA25 in spite of a lack of randomized clinical trials (RCT)26–28 (seeAntithrombotic therapy in patients with AF undergoing TAVI orLAAO section for NOACs and bioprosthesis).
BioprosthesesAfter biological valve replacement, thrombo-embolic risk is esti-mated between 0.6 to 3.3% per year without anticoagulation, after
the third month.29 The thrombo-embolic risk associated with a bio-prosthesis and sinus rhythm is higher in the first 3 months after sur-gery, the risk being almost eliminated in anticoagulated patients foraortic bioprosthesis, but remaining higher in patients with a mitralbioprosthesis.30,31 The benefit of an initial anticoagulant treatmentfollowing aortic valve replacement with a bioprosthesis and no AF ishowever debated.32–34
Overall AF patients with a bioprosthesis had a non-significantlyhigher risk of stroke/TE events compared with patients with non-valvular AF, and VKA use was independently associated with alower risk of thrombo-embolic events (hazard ratio 0.83, 95%CI 0.71–0.98).35
One small pilot study compared Dabigatran Versus Warfarin AfterBioprosthesis Valve Replacement for the Management of AtrialFibrillation Postoperatively (DAWA Pilot Study) but small numberspreclude definitive conclusions.36
Recent small studies also suggest that NOACs can be a reasonablealternative to VKA in patients with AF and remote bioprostheticvalve implantation,26,37 however larger studies are needed to definethe safety and efficacy profile. Data on thromboprophylaxis inpatients with AF and TAVI, which is actually the insertion of a bio-prosthesis, are preliminary38 and discussed in detail elsewhere in thedocument section.
Mitral valve repairPatients undergoing mitral valve repair have a small risk of TE,39 withthe highest risk of TE occurring during the first year after surgery.Guidelines therefore recommend OAC during the first 3–6 monthsafter surgery.40 However, only limited data are available on the effi-cacy of warfarin therapy in the early stages after valve surgery, andthe use of short-term VKAs in patients with mitral valve annuloplastyis also controversial. It is therefore not clear whether patients withAF in addition to valve repair are markedly different from the patientswith AF and no VHD.6,21
North American and European guidelines have a different positionon this issue, the former considering AF is ‘valvular AF’ whilst ESCguidelines do not.32,41
Table 2 Target international normalized ratio forsome examples of mechanical prosthesis
Prosthesis
thrombogenecity
Valve type Patient-related
risk factors*
Risk factor >_ 1
Low Carbomedics, Medtronic
Hall, St Jude Medical,
ON-X
3.0
Medium Other bileaflet valves 3.5
High Lillehei-Kaster,
Omniscience, Starr-
Edwards, Bjork-Shiley
and other tilting-disc
valves
4.0
*Risk factors: previous thromboembolism; AF; mitral stenosis of any degree; leftventricular ejection fraction < 35%. Reproduced from reference.24
1758d G.Y.H. Lip
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Consensus statements
Indications of ‘add on’ antiplatelettherapy in patients with atrialfibrillation and prostheticmechanical heart valves
Arterial TE and valve thrombosis are �12%/year and 22%/year, formechanical valve prosthesis in the aortic and mitral position, respec-tively, in patients without VKA prophylaxis.29 The residual risk rangesfrom 0.5%/year, to 2.5%/year,29,42–44 in VKA-treated patients withoutadditional cardiovascular risk factors such as AF. A higher incidence isassociated with the mitral (�2%/year) vs. the aortic (�1%/year) posi-tion, depending also on the type of valve and VKA intensity.29,43,44 AFand/or other risk factors (e.g. heart failure, even without AF) increaseTE risk by four-fold, from 4% up to 8%/year,45–47 even on adequateVKA treatment.45,46
Given this high residual TE risk, RCT have compared VKA alone vs.VKA combined with different aspirin doses and/or dipyridamole29,48,49
(Table 3).Despite major methodological limitations of these studies includ-
ing small sample size, heterogeneities in thrombotic risk level at studyentry and anticoagulation intensity, inconsistencies in safety and effi-cacy endpoint definitions,48 there may possibly be some benefit ofadding low-dose aspirin (between 75 and 200 mg daily) to VKA inpatients with mechanical valve prosthesis and additional risk factorsincluding AF29,48,54 (Table 3). This approach lowered TE complica-tions in the majority of studies,29,45,46,48,54 and two meta-analysesshowed�60% relative risk reduction (RRR) of TE and�50% RRR ofall-cause mortality48,49 (Table 3). Nonetheless, the relative risk ofmajor bleeding with VKAs plus antiplatelet therapy increases by�58% across studies including aspirin daily doses from 100 to1000 mg48,49 and high dose dipyridamole alone or with aspirin.48
Importantly, major bleeding appears significantly affected by aspirindose: the association with low dose (100 mg) shows a bleeding risksignificantly lower than higher doses50,52 and not significantly differentfrom VKA alone (OR = 0.96; 95% CI 0.60–1.55; 2.58; 95% CI 1.43–2.55 for low and high doses vs. VKA, respectively, P = 0.002 for thehigh aspirin dose combination vs. VKA) with similar efficacy(Table 3).48,50 Thus, VKA plus low-dose aspirin (75–100 mg daily) forthe association of mechanical prosthetic valve and AF, is
recommended by the AHA/ASA/ACCP as a class I (level A or B) rec-ommendation,42,44,55,56 but as a class IIb C recommendation by theESC.
When the aspirin/VKA combination is used, anticoagulation shouldbe titrated taking into account the type of valve, the position, andcomorbidities. The target INR for AF patients with aortic mechanicalprosthetic valve on VKA and low-dose aspirin should be 2.5 (range2.0–3.0), with close attention to the quality of anticoagulation con-trol, with time in therapeutic range (TTR) >65–70%. This applies tolow-thrombogenicity valves, including Carbomedics, Medtronic Hall,St Jude Medical, ON-X; but there is insufficient data for other valves,even if bileaflet.
Whether the INR target should be 2.5 (range 2–3) or 3 (range2.5–3.5) in AF patients with mitral prosthetic valve on both VKA andlow-dose aspirin is less clear. High intensity VKA (i.e. INR range 3–4or higher), combined with aspirin, has been consistently associatedwith higher major bleeding and comparable benefit as lower intensityVKA with aspirin.51,52,57
Consensus statements
Evidence for non-vitamin Kantagonist oral anticoagulants usein patients with atrial fibrillationand valvular heart disease
Subgroups from the recent non-vitaminK antagonist oral anticoagulant trialsThe efficacy and safety of NOACs for the prevention of stroke/sys-temic embolic events (SSEE) in patients with non-valvular AF hasbeen established by the pivotal randomized trials.58,60–63 These trialsexcluded patients with significant mitral stenosis or prostheticmechanical valves but enrolled participants (13–26%, depending on
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lus
asp
irin
inp
ati
en
tsw
ith
mech
an
icalvalv
ere
pla
cem
en
tsi
nce
1990
Refe
ren
ce
Desi
gn
Pati
en
tsA
Fan
dM
VR
po
siti
on
(%)
Eff
icacy
Safe
tyC
om
men
tso
rad
di-
tio
nald
ata
Tur
pie
etal
.45
RC
T:V
KA
(INR
targ
et
3–4.
5)þ
ASA
100
mg
daily
vs.V
KA
(INR
targ
et
3–4.
5)þ
plac
ebo
mea
nf.u
.2.5
year
s
370
patie
nts
with
MV
Ror
tissu
eva
lve
repl
acem
ent
þA
For
TE;
mea
nag
e58
year
s
mal
es50
%
AF:
45%
per
arm
;
Mitr
al44
%,
Aor
tic46
%
Mul
tiple
10%
Maj
orsy
stem
icem
bolis
m
orva
scul
arde
ath:
1.9%
/
year
ASA
vs.8
.5%
/yea
r
plac
ebo
NN
T¼
15
Maj
orbl
eedi
ng:8
.5%
/yea
r
ASA
,6.6
%/y
ear
plac
ebo
P=
0.43
;
NN
H¼
52
Mea
nIN
R:3
inea
char
m.
Net
bene
ficia
leffe
ctfa
v-
oure
dA
SA(R
RR
61%
)
Altm
an
etal
.50
RC
T:V
KA
(INR
targ
et2–
3)
plus
:ASA
100
mg
orA
SA
650
mg
daily
mea
nf.u
.20
mon
ths
416
patie
nts
with
mec
hani
-
calM
VR
;
mea
nag
e60
year
s
mal
es50
%
AF:�
23%
per
arm
Mitr
al26
%,
Aor
tic74
%
Maj
orT
E:0.
5%/y
ear
inlo
w-
ASA
and
1.1%
/yea
rhi
gh
ASA
;
Vas
cula
rde
ath
1.2%
/yea
r
low
-ASA
vs.0
.5%
/yea
r
high
-ASA
,P=
0.3
Maj
orbl
eedi
ng:3
.6%
/yea
r
low
-ASA
vs.5
.1%
/yea
r
high
-ASA
;
any
blee
ding
:7.9
%/y
ear
low
-ASA
vs.1
3.4%
/yea
r
high
-ASA
,
p=
0.03
;
Vas
cula
rm
orta
lity
and
non-
fata
lTE:
3.4%
low
-
ASA
and
2.9%
high
ASA
,
P=
n.s.
Mes
chen
gies
-
eret
al.5
1
RC
T:h
igh
inte
nsity
VK
A
(INR
3.5-
4.5)
vs.l
ess
inte
nse
VK
A(IN
R2.
5-3.
5)
þA
SA10
0m
g
med
ian
f.u.:
23m
onth
s
503
patie
nts
with
MR
V;
�30
%m
itral
MV
R
med
ian
age
53ye
ars
mal
es58
%
AF:
15%
high
VK
Aar
m;2
0%
VK
Aþ
ASA
arm
;p=
0.04
Mitr
al29
%
Aor
tic66
%
Mul
tiple
4%
Maj
orT
E:1.
48%
/yea
rhi
gh
VK
Avs
.1.3
2%/y
ear
VK
A
þA
SA,
P=
n.s.
Maj
orbl
eedi
ng:2
.23%
/yea
r
high
VK
Avs
.1.1
3%/y
ear
VK
Aþ
ASA
;p=
ns
GIb
leed
ing:
2.12
%/y
ear
high
VK
Avs
.0.7
6%/y
ear
VK
Aþ
ASA
,
P=
0.14
Mea
nIN
R:h
igh
VK
Aar
m
3.98
.
VK
Aþ
ASA
3.1
p<
0.00
1
Mor
talit
y:hi
ghV
KA
8.1%
vs.
VK
Aþ
ASA
3.5%
(RR
for
VK
Aþ
ASA
0.41
,95%
CI
0.23
-0.8
1)62
Laffo
rtet
al.4
6R
CT
:VK
Aþ
ASA
200
mg
daily
vs.V
KA
alon
e
INR
targ
et3
(2.5
-3.5
)f.u
.:
1ye
ar
229
patie
nts
with
MV
R;
mea
nag
e63
year
s
mal
es50
%
Non
-sin
usrh
ythm
:
�49
%pe
rar
m
Mitr
al:1
00%
Maj
orT
E:0.
9%A
SAþ
VK
A
vs.4
.1%
VK
A,P
=ns
.
Tot
alT
E:9%
ASAþ
VK
A
vs.2
5%V
KA
,P=
0.00
4;
NN
T¼6
Echo
card
iogr
aphi
cth
rom
bi
day
9:4.
8%A
SAþ
VK
Avs
.
13.1
%V
KA
,P=
0.03
Maj
orbl
eedi
ng:1
9.2%
ASAþ
VK
Avs
.8.3
%V
KA
,
P=
0.02
NN
H¼
10
No
sign
ifica
ntdi
ffere
nces
inm
orta
lity
(few
even
ts)
Lars
onan
d
Fish
er49
Met
a-an
alys
isof
4tr
ials
usin
gas
piri
n
869
patie
nts
Var
iabl
ede
pend
ing
onth
e
stud
y
Maj
orT
E:3.
5%V
KAþ
ASA
vs.1
1.3%
VK
Aon
ly
NN
T:13
Maj
orbl
eedi
ng:1
3.1%
VK
A
þA
SAvs
.8.1
%V
KA
only
NN
H:2
0
All-
caus
em
orta
lity:
5.4%
VK
Aþ
ASA
vs.7
.9%
VK
A
only
Asp
irin
daily
dose
rang
ed
from
100
to10
00m
g
Cont
inue
d
1758f G.Y.H. Lip
Downloaded from https://academic.oup.com/europace/article-abstract/19/11/1757/4098134by gueston 25 August 2018
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....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
.
Tab
le3
Co
nti
nu
ed
Refe
ren
ce
Desi
gn
Pati
en
tsA
Fan
dM
VR
po
siti
on
(%)
Eff
icacy
Safe
tyC
om
men
tso
rad
di-
tio
nald
ata
Peng
oet
al.5
2R
CT
:low
-inte
nsity
VK
A
(INR
2–3)þ
ASA
100
mg
vs.h
ighe
rin
tens
ityV
KA
(INR
2.5–
3.5)
for
6m
onth
s
f.u.:
1.5
year
s
198
patie
nts
with
MV
R;
mea
nag
e60
year
s
mal
es46
%
�28
%pe
rar
m
Mitr
al28
%
Aor
tic63
%
Mul
tiple�
10%
VK
Aþ
ASA
:4m
ajor
blee
d-
ing
and
1is
chae
mic
stro
ke;V
KA
:2m
ajor
blee
ding
and
2is
chae
mic
stro
ke,P
=0.
6
Cum
ulat
ive
endp
oint
of
maj
orbl
eedi
ngan
d
thro
mbo
sis
Ver
ysm
alls
tudy
with
shor
t
trea
tmen
tan
dlo
wnu
m-
ber
ofev
ents
Don
get
al.5
3R
CT
:VK
Aþ
ASA
75–
100
mg
vs.V
KA
alon
e
mea
nf.u
.:24
±9
mon
ths
1496
patie
nts
with
mec
hani
calM
VR
;
mea
nag
e35
year
s
mal
es40
%
AF:
40%
per
arm
Mitr
al83
%
Aor
tic43
%
Mul
tiple
:16%
Maj
orT
E:2.
1%V
KAþ
ASA
vs.3
.6%
VK
Aal
one,
P=
0.04
NN
T¼
66
Maj
orbl
eedi
ng:3
.5V
KAþ
ASA
vs.3
.7%
inV
KA
alon
e;P
=ns
NN
H¼
500
War
fari
ndo
se:2
.92
±
0.87
mg
inV
KAþ
ASA
and
2.89
±0.
79m
gin
VK
A
alon
e.
No
diffe
renc
esin
mor
talit
y
rate
Mas
sela
nd
Litt
le48
Met
a-an
alys
isof
RC
Tco
m-
pari
ngV
KA
alon
evs
.
VK
Aan
dan
tipla
tele
ts
4122
patie
nts
with
MV
Rin
aort
icor
mitr
alpo
sitio
n
orbo
th
Var
iabl
ede
pend
ing
onth
e
stud
y
Maj
orT
E:A
SAþ
VK
Avs
.
VK
Aal
one
OR
0.43
[95%
CI0
.32-
0.5]
P<
0.00
1
Maj
orbl
eedi
ng:A
ntip
late
let
þV
KA
vs.V
KA
alon
eO
R
1.58
[95%
CI1
.14–
2.18
]
P<
0.00
1
ASA
high
:OR
2.58
[95%
CI
1.43
–1.5
5]
ASA
100
mg:
OR
0.96
[95%
CI0
.6–1
.55]
Stat
istic
alin
tera
ctio
nhi
gh
vs.l
owP
=0.
04
Ove
rall
mor
talit
y:
OR
0.57
[95%
CI0
.42-
0.78
]
Maj
orbl
eedi
ngin
stud
ies
pre-
1990
:OR
2.34
[95%
CI1
.34–
4.08
]
afte
r-19
90:O
R1.
26[9
5%
CI0
.84–
1.89
]
Dat
aar
epr
esen
ted
as%
/yea
r,w
hene
ver
poss
ible
.NN
Tan
dN
NH
per
year
are
calc
ulat
edfo
rth
eco
mpa
riso
nsin
clud
ing
the
com
bine
dV
KAþ
antip
late
let
trea
tmen
tvs
.VK
Aal
one,
whe
neve
rpo
ssib
le.
AF,
atri
alfib
rilla
tion;
ASA
,asp
irin
;f.u
.,fo
llow
-up;
INR
,int
erna
tiona
lnor
mal
ized
ratio
;MV
R,m
echa
nica
lval
vere
plac
emen
t;N
NT
,num
ber
need
edto
trea
t;N
NH
,num
ber
need
edto
harm
;OR
,odd
sra
tio;R
CT
,ran
dom
ized
clin
ical
tria
l;R
RR
,re
lativ
eri
skre
duct
ion;
TE,
thro
mbo
embo
lism
;VK
A,v
itam
inK
anta
goni
sts.
Antithrombotic therapy in AF with valvular heart disease 1758g
Downloaded from https://academic.oup.com/europace/article-abstract/19/11/1757/4098134by gueston 25 August 2018
the trial)28,59,64,65 with other clinically significant non-rheumatic VHD,including mitral regurgitation (MR), aortic regurgitation (AR), aorticstenosis (AS), mild mitral stenosis (MS) or prior valve surgery (bio-prosthetic valves or valve repair) (Table 4). There are limited or nodata on other options, such as MitraClip or other TMVI, and thus,NOACs should not be used in these patients.
Variable inclusion/exclusion criteria across the NOACs trialsreflect the prevailing lack of a clear-cut definition of valvular AF.6
Patients with VHD of non-rheumatic origin are prevalent in clinicalpractice,66 and physicians may often deny NOACs to eligible AFpatients due to uncertainty over whether the patient has valvular ornon-valvular AF.3
There are no randomized trials on NOACs in AF patients withVHD. In the Randomized Evaluation of Long-Term AnticoagulationTherapy (RE-LY),59 Rivaroxaban Once Daily Oral Direct Factor XaInhibition Compared with Vitamin K Antagonism for Prevention ofStroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF),64
Apixaban for Reduction in Stroke and Other ThromboembolicEvents in Atrial Fibrillation (ARISTOTLE)65 and EffectiveAnticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48)28
trial subgroup analyses, non-valvular AF patients with VHD wereolder, had more comorbidities (including renal dysfunction), morepersistent/permanent AF and higher cardioembolic and bleeding risksthan patients without VHD. Whilst the use of aspirin was broadly
similar, prior VKA use was more common among patients with VHD.Irrespective of the treatment arm (i.e. warfarin or a NOAC), VHDpatients generally experienced worse outcomes (stroke and systemicTE, major bleeding or all-cause death) in comparison to non-VHDpatients (Table 5). Nonetheless, the efficacy of NOACs in reductionof SSEE or all-cause mortality was consistent among patients withoutor with VHD (irrespective of the VHD subtype). Likewise, the safetyof NOACs in terms of lower risk of major bleeding or ICH was con-sistent irrespective of VHD status, excluding the significantly higherrates of major bleeding in VHD patients (particularly those withaortic stenosis, or mitral or aortic regurgitation)69 treated with rivar-oxaban compared to warfarin (Table 5). Importantly, there are nohead-to-head comparisons for any NOAC vs. VKA in AF patientswith moderate to severe mitral stenosis; as mentioned, these patientswere not enrolled in the NOACs trials.
The number of patients with any prior valve surgery (i.e. bio-prosthetic valves or valve repair) exposed to rivaroxaban, apixa-ban or edoxaban in the ROCKET-AF, ARISTOTLE or ENGAGEAF-TIMI 48 trials, respectively, was very low (Table 4).Nevertheless, as reported for apixaban and edoxaban,26,68 therewas no statistically significant interaction between the presence ofa bioprosthetic heart valve and the respective NOAC effects(Table 5), thus suggesting that apixaban or edoxaban may possiblybe alternatives to warfarin in AF patients with bioprosthetic valvesimplanted >_3 months ago.
Table 4 Inclusion/exclusion criteria pertinent to valvular heart disease in the pivotal NOAC trials in patients with‘non-valvular’ AF and valvular disease type distribution across the trials
Moderate/severe AR 817 (20.7) 486 (24.3) 887 (18.4) 369 (13.0) NR
Moderate/severe AS 471 (11.9) 215 (10.7) 384 (8.0) 165 (5.8) NR
Other 1179 (6.5) 11 (0.6)d 2124 (44.2) NR NR
Mild MS 193 (4.9) NR 131 (2.7) 254 (9.0) NR
Prior valve surgery (excluding mechanic
prosthetic heart valve)
Not applicable 106 (5.3) 251 (5.2) 325 (11.5) NR
Valve repair — 42 (2.1%) NR 123 (4.3) NR
Valvuloplasty — 64 (3.2%) NR 19 (0.7) NR
Bioprosthetic valves — Not applicable 82 (1.7) 191 (6.8) NR
AF, atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; MR, mitral regurgitation; MS, mitral stenosis; NOAC, non-vitamin K antagonist oral anticoagulant; NR, notreported.aAnnuloplasty, Commisurotomy, Valvuloplasty, etc.bClinically significant, but not requiring immediate surgery repair.cCategories are not mutually exclusive.dWithout any of the preceding.
1758h G.Y.H. Lip
Downloaded from https://academic.oup.com/europace/article-abstract/19/11/1757/4098134by gueston 25 August 2018
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....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
....
Tab
le5
Majo
ro
utc
om
es
inA
Fp
ati
en
tsb
yvalv
ula
rh
eart
dis
ease
statu
san
dtr
eatm
en
t
Ou
tco
me
tria
lN
OA
C/W
arf
ari
nV
HD
(Rate
%/y
ear)
No
VH
D
(Rate
%/y
ear)
VH
DN
OA
Cvs.
warf
ari
nH
R(9
5%
CI)
No
VH
DN
OA
Cvs.
warf
ari
nH
R(9
5%
CI)
Inte
racti
on
P
Stro
ke/S
E
RO
CK
ET-A
F64
Riv
arox
aban
/War
fari
n2.
01/2
.43
1.96
/2.2
20.
83(0
.55–
1.27
)0.
89(0
.75–
1.07
)0.
70
AR
IST
OT
LE65
Api
xaba
n/W
arfa
rin
1.46
/2.0
81.
20/1
.43
0.70
(0.5
1–0.
97)
0.84
(0.6
7–1.
04)
0.37
8
RE-
LY59
Dab
i-150
mg/
War
fari
n1.
12/1
.90
1.11
/1.6
60.
59(0
.37–
0.93
)0.
67(0
.52–
0.86
)0.
63
Dab
i-110
mg/
War
fari
n1.
84/1
.90
1.45
/1.6
60.
97(0
.65–
1.45
)0.
88(0
.70–
1.10
)0.
65
ENG
AG
E-A
F28
HD
ER/W
arfa
rin
1.39
/2.0
2
1.94
/2.0
2
1.60
/1.7
7
2.04
/1.7
7
0.69
(0.4
4–1.
07)
0.97
(0.6
6–1.
44)
0.91
(0.7
7–1.
07)
1.15
(0.9
8–1.
35)
0.25
5
0.44
0LD
ER/W
arfa
rin
AR
IST
OT
LE67
biop
rost
hetic
valv
es(n
=82
)A
pixa
ban/
War
fari
n2.
9/0.
0N
AN
RN
A—
ENG
AG
E-A
F26
biop
rost
hetic
valv
es(n
=19
1)H
DER
/War
fari
n1.
19/1
.66
NA
0.37
(0.1
0–1.
42)
NA
0.15
LDER
/War
fari
n2.
57/1
.66
NA
0.53
(0.1
6–1.
78)
NA
0.31
Maj
orbl
eedi
ng
RO
CK
ET-A
F64
Riv
arox
aban
/War
fari
n6.
14/4
.20
3.22
/3.3
31.
56(1
.14–
2.14
)0.
98(0
.84–
1.15
)0.
01
AR
IST
OT
LE65
Api
xaba
n/W
arfa
rin
2.49
/3.1
42.
01/3
.07
0.79
(0.6
1–1.
04)
0.65
(0.5
5–0.
77)
0.23
RE-
LY59
Dab
i-150
mg/
War
fari
n4.
21/5
.12
3.06
/3.1
40.
82(0
.64–
1.06
)0.
98(0
.83–
1.15
)0.
25
Dab
i-110
mg/
War
fari
n3.
77/5
.12
2.63
/3.1
40.
73(0
.56–
0.95
)0.
84(0
.71–
0.99
)0.
38
ENG
AG
E-A
F28
HD
ER/W
arfa
rin
3.28
/4.4
6
1.82
/4.4
6
2.66
/3.2
7
1.59
/3.2
7
0.74
(0.5
3–1.
02)
0.41
(0.2
8–0.
60)
0.82
(0.7
1–0.
94)
0.49
(0.4
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Antithrombotic therapy in AF with valvular heart disease 1758i
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A meta-analysis70 of the VHD sub-groups from the RE-LY,ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI 48 trials broadlyconfirmed the findings shown in Table 5. Overall, AF patients withVHD had non-significantly higher rate of SSEE (RR 1.13; 95% CI,0.99–1.28) and significantly higher rates of major bleeding (RR 1.34;95% CI, 1.13–1.49) and all-cause death (RR 1.34; 95% CI, 1.13–1.59)than patients without VHD.
Compared with warfarin, the use of NOACs (i.e. rivaroxaban,apixaban or higher doses of dabigatran or edoxaban) was associatedwith consistently lower rates of SSEE regardless of the presence orabsence of VHD (RR 0.70; 95% CI, 0.58–0.86 and 0.84; 95% CI, 0.75–0.95, respectively; interaction P = 0.31), similar major bleeding rates(VHD RR 0.93; 95% CI, 0.67–1.27 and no-VHD RR 0.85; 95%CI 0.70–1.02, interaction P = 0.63), consistently lower rates of ICH(VHD RR 0.47; 95% CI, 0.24–0.93 and no-VHD RR 0.49; 95%CI, 0.41–0.59, interaction P = 0.91) and higher all-cause death rate inVHD patients (RR 1.01; 95% CI, 0.90–1.14) than in those withoutVHD (RR 0.88; 95% CI, 0.82–0.94), interaction P = 0.03,70 In the anal-ysis that also included the lower doses of dabigatran and edoxaban,the magnitude of SSEE risk reduction with NOACs vs. warfarin wasslightly reduced, as well as the rates of major bleeding and ICH, butthere were no significant subgroup interactions by VHD status.Overall, the presence of VHD did not affect the relative protectiveeffect of NOACs compared with warfarin in terms of SSEE andmajor bleeding. These findings were further supported by anothermeta-analysis of the four NOACs yielding identical results.71 Of note,both meta-analyses reported significant treatment effect heterogene-ity regarding the analysis of major bleeding.
With the exclusion of patients with moderate-to-severe mitralstenosis, prosthetic mechanical heart valve, TAVI or TMVI, whowere not enrolled in the non-valvular AF trials, the aforemen-tioned subgroup and meta-analyses may suggest that AF patientswith VHD would experience at least the same benefit fromNOACs as patients without VHD. However, due to limitationsinherent to these types of analyses, further RCTs are required inAF patients with VHD before recommendations can be given (seeTables 4 and 5).
Prosthetic mechanical heart valves:Randomized, Phase II Study to Evaluatethe Safety and Pharmacokinetics of OralDabigatran Etexilate in Patients afterHeart Valve ReplacementMechanical valve prosthesis trigger complex mechanisms of throm-bogenesis and are associated with a very high cardioembolic riskrequiring chronic OAC even in the absence of AF. Animal studies onmechanical valve implantation using first the direct FIIa inhibitors mel-agatran72 and then dabigatran73,74 as well as the phase III data fromthe RE-LY trial61 informed the only study to date on a NOAC inpatients with mechanical heart valves.
The Randomized, Phase II Study to Evaluate the Safety andPharmacokinetics of Oral Dabigatran Etexilate in Patients afterHeart Valve Replacement (RE-ALIGN) trial was a phase-II, con-trolled, dose-finding, open-label study75 randomizing (2:1)patients with aortic (n = 172; 68%) or mitral (n = 71; 28%) mechan-ical valve replacement, or both (n = 9; 4%) to dabigatran or
adjusted-dose warfarin (target INR 2.0–3.0 or 2.5–3.5 in aortic ormitral position, respectively). The initial dabigatran dose of 150,220, or 300 mg b.i.d. (selected according to renal function) wasfurther adjusted over 12 weeks to achieve the primary study out-come—a trough plasma concentration >_50 ng/mL, based on thepharmacokinetic model from the RE-LY trial. Most patients (79%)received study drug 5–7 days after surgery, and 23% of patientshad AF. The RE-ALIGN study was prematurely terminated afterrandomizing 252 of 405 planned patients, due to an excess instroke (5% vs. 0%), valve thrombosis (3% vs. 0%) and major bleed-ing events (4% vs. 2%) in the dabigatran arm, after a mean dabiga-tran exposure of �20 weeks. Different explanations have beenproposed, including inadequate dabigatran plasma concentrations,different pharmacodynamics of dabigatran and warfarin, excessiveactivation of the contact coagulation pathway induced by the sew-ing ring in the early postoperative course, a higher inter-individualvariability in the dabigatran arm and differences in predicted vs.observed drug concentrations in the RE-LY vs. RE-ALIGN.75 Arecent in vitro study suggested that the dabigatran trough plasmaconcentration required to reduce valve-induced FIIa generationshould be much higher than 50 ng/mL (that is, 260 ng/mL) corre-sponding to a 620 mg b.i.d. dosing.68 At present, all AF patientswith a mechanical valve prosthesis should be treated with VKAsConsensus statements
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Antithrombotic therapy inpatients with atrial fibrillationundergoing trans-aortic valveintervention or left atrialappendage occlusion
Trans-aortic valve interventionprocedureMost ischaemic events after TAVI are cerebrovascular, and for theseAF is a strong contributor.77 AF is common among high-risk patientswith severe aortic stenosis undergoing TAVI, and is associated with a>2-fold increased risk of all-cause and cardiovascular death, irrespec-tive of the type of AF.78 In addition, the implanted valve adds aprothrombotic environment, which would accentuate the cardioem-bolic risk. Of importance, the gradient of risk directly correlates withthe CHA2DS2-VASc score, which is usually used to aid decision-making as whether to initiate OAC.77 At least 30% of the TAVI popu-lation requires OAC,1 a strategy that seems underused and that hasnever been evaluated prospectively. Dual antiplatelet therapy(DAPT) remains the most widely used antithrombotic strategy afterTAVI, being used in >60% of patients, while VKA is used in <20% ofpatients,77 although AF is observed in >40% of TAVI patients.Current recommendations are expert-driven, rather than evidence-based (Table 6).
Up to 35% patients undergo coronary stenting prior to TAVI. Insuch patients, the risk of stent thrombosis and/or ischaemic cardiacevents in addition to that of AF should be considered in the overallrisk assessment.82 Here triple therapy, a combination of a VKA, low-dose aspirin and clopidogrel, is used in high risk patients, and associ-ated with an increased risk of death, stroke, TE, or major bleedingwhen compared to VKA alone.78,82 Such combinations should be
discussed in the context of recent (i.e. <6 months) acute coronarysyndrome and/or stent implantation, especially in the presence of anunfavourable coronary anatomy (more than three stents, stentlength >_60 mm, multivessel disease, left main disease) but should beavoided whenever deemed possible given the established bettersafety and the possible preserved efficacy of a combination of war-farin and clopidogrel in patients with AF undergoing drug-elutingstent placement.83–85
Recent evidence suggests that VKA alone is much safer and pro-vides a similar rate of ischaemic events as compared to VKA plus anti-platelet therapy (aspirin) in patients undergoing TAVI.82 Howeverthis study was observational, not randomized with an unbalancednumber of patients per treatment arm, and randomized confirmationis needed. Therefore, the association of OAC with SAPT in AFpatients who underwent successful TAVI should be considered up toone year when there is a recent ACS or a recent coronary stenting86
and when the bleeding risk is deemed low (Figure 2).OAC alone as antithrombotic strategy is currently being tested
in three trials (POPular-TAVI NCT02247128, GALILEONCT02556203, ATLANTIS trial NCT02664649), while another trialis testing aspirin alone or in combination with clopidogrel (ARTENCT02640794), although AF patients appear excluded. Indeed, thebenefit of VKA over DAPT in AF depends on the quality of INR con-trol,76 and it has been modelled that a time in therapeuticrange >_58% would be needed to benefit from being on OAC ratherthan on DAPT,76 which is probably not the case in the TAVIpopulation.
Subclinical valve thrombosis is another challenging issue as it maymay occur early after TAVI. Although the frequency of this poten-tially ominous phenomenon remains undefined, as this condition isdifficult to detect, but it seems reversible with anticoagulation.Whether it is associated with cerebrovascular events remains to beestablished.87 Given all these uncertainties, ongoing trials are alsotesting the anticoagulation hypothesis after successful TAVI irrespec-tive of the need of OAC hypotheses using NOACs (NCT02556203,NCT02664649) which have been shown to be better tolerated.Figure 2 shows all currently recommended treatment options.
Recent observational evidence suggest the safety of FXa inhibitionin TAVI,88 showing the feasibility of NOAC in the post-TAVI setting.However, results from randomized comparison of FXa inhibition vs.other antithrombotic strategies are lacking.
Left atrial appendage occlusionprocedureFollowing clinical trials,89–91 percutaneous endovascular left atrialappendage occlusion (LAAO) has been increasingly developed andperformed worldwide for patients with AF, especially those withcontraindications to long-term OAC.92,93 This is supported by guide-lines from the ESC, which give a class IIB recommendation for LAAOin AF patients with high stroke risk and contraindications to long-term OAC.4
Antithrombotic therapy following LAAO has not been well eval-uated, and it is not even known whether OAC or antiplatelet therapyor no therapy is preferable. When possible according to the patientbleeding risk profile, after LAAO most centres use a 6-week periodof VKA (target INR 2.5) followed by once daily clopidogrel (75 mg)
NOACs in this setting.• The efficacy and safety of NOACs in
patients with non-rheumatic mitral
and/or aortic regurgitation or other
native VHD may be similar to AF
patients without VHD based on small
numbers of patients in post hoc analy-
ses of RCTs. More data are needed to
define the role of NOACs in this
setting.
9,66–72,77,78
• In patients with haemodynamically
insignificant valve disease and in those
who have had prior successful balloon
mitral valvulotomy, NOACs can be
considered as substitute for VKAs.
67,68,71–75,77
NB. Recommendations for TAVI are given in the specific section.
Antithrombotic therapy in AF with valvular heart disease 1758k
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and aspirin (75–325 mg) until the 6-months visit. Some patients mayalso receive NOAC.94 Subsequently, low-dose aspirin alone iscontinued indefinitely, as tested in the pivotal trials.89,90,95 This anti-platelet regimen has never been compared with any long termNOAC-based anticoagulation regimen.9,96 However, the ASAP studyshowed that LAAO with the Watchman device is feasible and could
be safely performed without OAC cover (but with antiplatelet ther-apy).95 Such strategy is being evaluated in the ongoing ADRIATICstudy (Apixaban versus Dual or single antiplatelet therapy to ReduceIschemic and bleeding events in Atrial fibrillation patients Treatedwith Invasive Closure of the left atrial appendage). The ASAP TOOrandomized trial (NCT02928497) is currently establishing the safety
Table 6 Recommendations for antithrombotic therapy during and after TAVI in the guidelines in patients with andwithout indication for OAC
ACC/AHA/STS79 ESC80 ACCP44 CCS44,80
Procedural Unfractionated Heparin
(ACT> 300 s)
– –
Post-procedural Aspirin 81 mg indefinitely
and Clopidogrel 75 mg
for 3 up to 6 months
Aspirin (or clopidogrel)
indefinitely
Aspirin (50–100 mg/day)
and Clopidogrel
(75 mg/day) in the first
3 months
Low-dose Aspirin indefi-
nitely and 1–3 months
of a thienopyridine
(no evidence).
Aspirin and clopidogrel
in first 3 months after
TAVI
Patients with a clear
indication for OAC (as
in AF)
It is reasonable to con-
tinue low-dose Aspirin,
but other antiplatelet
therapy should be
avoided
No antiplatelet therapy
but OAC alone
No recommendation Adjunctive antiplatelet
agents is controversial
and triple therapy
should be avoided
ACC, American College of Cardiology; ACT, activated clotting time; ACCP, American College of Chest Physicians; AF, atrial fibrillation; AHA, American Heart Association;ASA, acetylsalicylic acid (aspirin); AVR, aortic valve replacement; CCS, Canadian Cardiovascular Society; ESC, European Society of Cardiology; INR, international normalizedratio; VKA, vitamin K antagonists.
Figure 2 Proposed algorithm for AF patients undergoing a TAVI procedure (adapted from references 87). O refers to oral anticoagulation as VKA(or possibly NOAC). ASC, acute coronary syndrome; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant;SAPT, single antiplatelet therapy.
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and effectiveness of the LAAO vs. SAPT in patients with non-valvularAF deemed not to be eligible for OAC to reduce the risk of stroke.Consensus statements
Antithrombotic therapy forvalvular atrial fibrillation inpregnant women
Valvular AF in pregnancy is relatively rare and can be due to congenitalheart disease, mitral valve prolapse with significant mitral regurgitation,or to rheumatic heart disease. Valves can be repaired or replaced witha mechanical valve prosthesis.97 Pregnancy by itself is a prothromboticstate and the coalescence of venous stasis and hypercoagulabilityresults in nearly a five-fold increase in the risk of venous thromboemb-olism during pregnancy.86 The goal of anticoagulation during pregnancyshould be to safely balance the maternal risk of TE and haemorrhagewith the foetal risk of exposure to VKA. The continuously changingpharmacokinetics of LMWH during the various trimesters adds anadditional challenge and requires monitoring by peak and trough anti-Xa levels,86 which is often not feasible (Figure 3).
Women of child-bearing age with VHD need to be comprehen-sively counselled prior to valve replacement and pre-pregnancy todecide on the most appropriate type of valve and to be made awareof the teratogenicity and fetotoxicity of VKA, pregnancy-induced hae-modynamic changes and the pre-existing hypercoagulable statewhich can compromise foetal development and significantly increasethe risk of serious and/or fatal complications to both mother andchild.98 Women with mechanical prosthetic valves should ideally
have preconception evaluation, including advice on risk predictionand contraception, by a joint cardiac-obstetric team seeking advicefrom other specialties.97 Careful counselling on maternal and off-spring risk should be done according the modified World HealthOrganization classification and should include information on compli-cations such as heart failure, valve thrombosis, bleeding complicationswhich can occur during, but also beyond the immediate deliveryperiod. Also, the consequences of the medication that may berequired (for example warfarin embryopathy) need to be discussed.However, often women in some countries may present after20 weeks of gestation, which has implications for their functionalassessment, harmful medication can’t be terminated timeously andlimits the option for pregnancy termination. Such cases are challeng-ing and should be managed at tertiary centre where they can beappropriately assessed and guided/treated. Since anticoagulation isrecommended in pregnant women with AF at risk of stroke, to mini-mise teratogenic risk and intrauterine bleeding, the ESC guidelinesrecommend that dose adjusted heparin should be used during thefirst trimester of pregnancy and in the 2–4 weeks before delivery.4
VKA or heparin can be used in the remaining trimesters of the preg-nancy.4 In the absence of adequate safety data, NOACs should beavoided in pregnancy and in women planning a pregnancy4.Consensus statements
Patient values and preferences,and societal issues
Treatment decisions need to balance the benefits and risks of treat-ment and manage realistic patient expectations, particularly in associ-ation with co-morbidities and in pregnancy. These decisions arecomplex and require assimilation of life expectancy, ability and will-ingness to take anticoagulants, risk of bleeding, lifestyle, co-morbidities, risk of re-operation, and patient preference.100–102
Clinical guidelines on the management of VHD100 advocate incor-porating informed patient preferences into treatment decisions andtechnological advances (for VHD) must be employed ‘responsiblywithin a framework of care which enables shared decision makingand promotes patient goals and well-being’.103 This requires candiddiscussions between the patient and physician to ensure that
Antithrombotic therapy in AF with valvular heart disease 1758m
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treatment is not futile. Shared decision making103,104 requires patientsto be appropriately informed about treatment options and likely out-comes, to have the type of patient-physician relationship wherepatients feel able to ask questions and where physicians provideinformation and communicate risk effectively,105,106 to enablepatients to make an informed decision incorporating their values,goals and preferences.103,107,108 Patient’s treatment preferences arelikely to vary markedly, with patients often willing to accept higherlevels of risk.108 Patient decision-aids including micro-simulationmodels are available for patients with VHD.109,110
Implications for low-to-middle incomecountriesValvular AF is more common in the Asian and African populationcompared to their western counterparts mainly due to greater bur-den of rheumatic heart disease.110,111,112 Stroke risk is higher amongpatients with valvular AF (17–18%/year) compared to those withnon-valvular AF (4%/year).113 Further, AF may further increase therisk of bioprosthetic valve thrombosis (see Supplementary materialonline, Table S4).114 The burden of rheumatic valve disease is higher,but the quality of anticoagulation is suboptimal in low and middleincome countries. Monitoring of the INR and follow-up remains poorand significant proportion of patients present with sub-therapeutic
INR. The majority of these patients are young (median age28 years),118 unemployed (75.3%) and women (51–66%)112,115 ofreproductive age. On average, they tend to be nearly 10–12 yearsyounger than their western counterparts. Many are unaware of theconcept of therapeutic range INR (60%) and few (<4%) are on con-traceptives despite treatment with warfarin. The NOACs are expen-sive and beyond the reach of the majority of patients requiring themin these countries. Suboptimal anticoagulation and consequentincreased risk of stroke, may lead to significant disability adjusted lifeyears lost and this is likely to pose a major economic burden.Strategies to improve awareness: (i) about the disease, (ii) medicationside-effects, (iii) importance of medication adherence and INR moni-toring, and 4) the danger of anticoagulation during pregnancy arescanty. Although point of care INR testing shows promise (seeSupplementary material online, Table S4), its use among patients fromthe developing world needs to be determined. The impact ofNOACs is less certain, although one recent Brazilian study evaluatingNOACs in public health system context found that NOACs presenta lower cumulative cost per patient when compared to VKAs.116
Health economic perspectivesAF is a disease that induces significant consumption of resources andcosts, encompassing direct medical costs, associated with patient’s
Figure 3 Management strategies for women with mechanical valve prosthesis. CCF, congestive heart failure; ICU, Intensive Care Unit.
1758n G.Y.H. Lip
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medical care (hospitalisations, medications, out-patient visits, etc.),and direct non-medical costs (i.e. costs related to residential or socialcare, as well as out of pocket expenses).117,118
Other costs that are usually taken into account in health-economic analyses are productivity losses caused by patients’ inabilityto work, or absence from work of relatives in order to provide infor-mal care.119 In patients with AF direct costs, reported as per-patientannual costs, have been estimated $2000 to 14 200 in NorthAmerica and 450 to 3000 Euros in Europe per patient.119
Patients with VHD who have AF require appropriate risk stratifica-tion for stroke/SE and, when indicated, the consequent prescriptionof OAC implies a difficult balance between the risk of stroke and sys-temic TE and the risk of bleeding.120,121 Stroke and major bleedinghave also an economic effect. Indeed, the main drivers of costs in AFpatients are AF-related hospitalizations, stroke and haemorrhagicevents. For strokes occurring in patients with AF, the direct costs perpatient are approximately 33% greater than the costs of stroke not-related to AF126 and are in the range of 30 000 Euros over a 2-yearperiod for a severe ischaemic stroke.123 The costs of intra-cerebralhaemorrhage is 50% higher than the cost of ischaemic stroke over a1 year time course.124
Underutilization of, and non-adherence to, warfarin is also quitecommon and is associated with increased costs,125,126 resulting fromTE and haemorrhagic complications. Improved adherence to OAC inAF patients at risk of stroke is important in order to attain the fullclinical and economic benefit of thromboprophylaxis.
Non-vitamin K antagonist oral anticoagulants can be prescribed tosome subgroups of patients with VHD6,127,128 and a series of analysesfocusing on the cost-effectiveness of these agents vs. warfarin hasbeen published, although no study considered separately patientswith VHD. In general, despite the higher cost of NOACs as com-pared to warfarin, the associated benefits make these agentscost-effective in the long-term, especially in settings with poor antico-agulation control associated with VKAs.129,130
Consensus statements
Summary and areas for futureresearch
Mechanical valve prosthesesCurrently, patients with AF and a mechanical prosthesis should onlybe treated with a VKA. Since the RE-ALIGN study, no other NOAC(factor Xa inhibitor drug class) has been tested in this patient group.75
However, the thrombotic risk could be reduced once endothelial tis-sue is present around the ring.17 A trial could potentially be designedafter endothelialization: the first 3 months with VKA, followed by arandomized comparison between continuing VKA or switching to aNOAC.
One trial proposed or ongoing with NOACs in patients with andwithout AF, is the Comparison of Antithrombotic Treatments AfterAortic Valve Replacement. Rivaroxaban: A New AntithromboticTreatment for Patients With Mechanical Prosthetic Aortic HeartValve: CATHAR trial(https://clinicaltrials.gov/ct2/show/NCT02128841?term=rivaroxabanþandþmechanicalþvalve&rank=2).
Bioprostheses, trans-aortic valveintervention, and transcatheter mitralvalve interventionsUsually, patients with a bioprosthesis and AF receive a VKA.Pericardial valves are less thrombogenic than mechanical valve pros-theses. Some physicians do not consider bioprostheses as a contra-indication of NOACs. Before recommending a NOAC rather thanVKA for these patients, a randomized trial is needed. This is also thecase for patients undergoing valve repair.
Trans-aortic valve intervention corresponds to transluminal implan-tation of a bioprosthesis and is being increasingly used. The antithrom-botic treatment in patients with sinus rhythm and TAVI remainscontroversial and the optimal treatment in patients with AF requiringTAVI (as well as TMVI—see earlier section) is currently unknown.
A global study comparing a rivaroxaban-based anti-thromboticstrategy to an antiplatelet-based strategy after TAVI to optimizeclinical outcomes (GALILEO) is currently ongoing.131 The twoarms consist of either rivaroxaban 10 mg once daily and aspirin75–100 mg for the first 90 days, followed by rivaroxaban alone; orclopidogrel 75 mg and aspirin 75–100 mg for the first 90 days, fol-lowed by clopidogrel alone. Patients with current or previous AFare excluded. The investigators assume that 15% of patients insinus rhythm at inclusion will develop AF during follow-up.Treatment after new onset AF will be, in patients randomized torivaroxaban, a switch to rivaroxaban 20 mg OD or 15 mg OD forthose with moderate renal impairment and in those randomizedto clopidogrel, a switch to VKA (target INR 2–3).
Another ongoing study is the Anti-Thrombotic Strategy afterTrans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS)study which is ongoing and plans to include 1509 patients aftersuccessful TAVI procedure. Randomization will be stratifiedaccording to the need for oral anticoagulant. Patients with an indi-cation for OAC will be randomized 1:1 to VKA or apixaban 5 mgb.i.d. The primary endpoint after 1 year follow-up is a compositeof death, myocardial infarction, stroke, systemic embolization,intracardiac or bioprosthesis thrombus, episode of deep veinthrombosis or pulmonary embolism, and major bleeding. Patientswith no indication for oral anticoagulant therapy will be random-ized 1:1 to either apixaban 5 mg bid or antiplatelet therapy. Othertrials are also proposed or ongoing with NOACs in patients withand without AF, include the RIvaroxaban for bioprostheticValvular Heart diseasE and atRial Fibrillation Trial (Warfarin vs.Rivaroxaban): RIVER Trial.
Antithrombotic therapy in AF with valvular heart disease 1758o
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Native valve diseasesThe main phase III studies of NOACs have used variable criteria forexcluding valvular patients. Some studies (ROCKET-AF andARISTOTLE) only excluded patients with mechanical valve prosthe-ses and significant (moderate to severe) mitral stenosis. The sub-analyses did not show any differences in efficacy among patients withand without VHD. In the ROCKET-AF, there was more bleeding onrivaroxaban than on VKA in patients with VHD.
A report from the Loire Valley Atrial Fibrillation Project comparedthe outcome of patients without any valve disease and those withvalve disease but did not include either valve prosthesis or mitralstenosis. Although patients with VHD had a higher risk of stroke andTE events on univariable analysis, the difference was no longer signifi-cant after adjustment, in line with an older age and a higherCHA2DS2-VASC score in patients with VHD.128
However, post hoc analyses are only hypothesis generating. LargeRCTs are needed with NOACs in the setting of AS, non-rheumaticAR and MR before the role of NOACs can be fully defined in thissetting.
Mitral stenosisThere has not yet been a randomized trial comparing VKA andNOACs in these patients. The prevalence of rheumatic mitral steno-sis has become low in Western countries but remains high in EasternEurope, India, Africa, South America, and south East Asia. In theseregions, the time in therapeutic range is only 35–44%, according to aglobal AF registry.7 Randomized clinical trials comparing VKA with aNOAC is highly welcomed and should preferably include patientsfrom these affected countries.
Supplementary material
Supplementary material is available at Europace online.
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